Innate immunity, as the first line of defense against microbial pathogens, is a response that must be tightly regulated or excessive inflammation will ensue, causing disease. For an optimal therapeutic approach, we need to not only understand basic mechanisms of initiation and early events that lead to disease but importantly, how the body protects itself from aberrant immune responses that can trigger autoimmunity. Uveitis (intraocular inflammation), which occurs in association with a number of systemic immunological diseases, presents a considerable medical challenge due to incomplete understanding of its pathogenesis. The gene NOD2 may provide an important clue into uveitis because a single point mutation results in a rare, inflammatory disease called Blau syndrome, which manifests as granulomatous uveitis. NOD2 belongs to a family of innate immune receptors termed NOD-like receptors (NLRs), which are intracellular sensors involved in host defense against invading pathogens. Since no other single gene has been identified as a singular cause of uveitis, analysis of NOD2-pathways could offer important insight into the underlying mechanisms controlling ocular inflammation. To understand how the endogenous, innate immune receptor NOD2 participates in orchestration of autoimmune responses, we undertook studies using experimental autoimmune uveitis (EAU), a prototypical T cell-mediated autoimmune disease model of the eye. Our preliminary studies led us to the unanticipated discovery that NOD2 deficiency renders mice susceptible to EAU; thereby identifying NOD2 as a major genetic susceptibility factor in autoimmune uveitis. Objectives outlined in this grant will test the centra hypothesis of this proposal that NOD2 is important for maintaining ocular immunological homeostasis by preventing aberrant responses that predispose to autoimmune disease of the eye by: (1) Maintaining proper regulation of T cell effector responses and diverting a pathogenic Th17-effector response; (2) Interpreting microenvironment cues within the eye by controlling the physiological state of microglia; and (3) Minimizing tissue damage caused by hypersensitivity responses involving the Fc-gamma receptor (FcgR) and complement systems that occur in the context of antibody-related activation. The goal of this project is to address currently unanswered questions within the field pertaining to the influence of innate immune receptors and orchestration of autoreactive T cell-driven responses. By focusing on aspects of how NOD2 controls early and innate reactions that exist at the interface of innate and adaptive immunity we hope to identify ways to enhance protective innate defenses within the eye while avoiding maladaptive effects of inflammatory pathology, as a potential novel strategy for therapeutic intervention for uveitis and other potentially vision-threatening diseases.